Diffuse endocrine systems: many hormone-producing cells are not aggregated in glands, but dispersed (e.g. in the gut)

Neuroendocrine systems: some neurones release hormones into both the bloodstream and into the CNS.

Classical endocrine action is when a chemical messenger (the hormone), released by a cell, is transported, via the bloodstream, to its target cell. This is now known to be much too narrow a concept because hormones act via various routes:

Neuroendocrine: the hormone is released from a neurone into the bloodstream

Paracrine: the hormone acts on local cells via the extracellular fluid

Autocrine: the hormone acts on the cell producing the hormone.

P.571 Major roles and characteristics The endocrine system promotes survival of the species by:

Promoting survival of the individual

Effects on development, growth, and differentiation

Help in preservation of a stable internal environmentâhomeostasis (but this is often disturbed short term for long-term gain)

Proteins/peptides/glycopeptides (hydrophilic) are translated on the rough endoplasmic reticulum and secreted by either the regulated pathway (e.g. insulin, prolactin) or the constitutive pathway (cytokines, growth factors). The original translation product (the prohormone) is usually processed proteolytically to yield the active hormone(s). Some endocrine cells produce more than one active peptide hormone, in varying amounts. Stored in large amounts in intracellular granules, but some peptides (e.g. growth factors and cytokines) are not stored. Steroids (hydrophobic e.g. testosterone, estrogen) are synthesized rapidly on demand (not stored) from cholesterol, via enzymes in the mitochondria and smooth endoplasmic reticulum. Bioactive amines (hydrophilic e.g. adrenaline, dopamine) are produced from tyrosine via intracellular enzymes. They are stored in large amounts in intracellular granules. Thyroid hormones (hydrophilic e.g. thyroxine) are iodothyronines produced by iodination and coupling of tyrosyl residues in a protein (thyroglobulin) which are then released by proteolysis. Large amounts of iodinated thyroglobulin, (the precursor for thyroid hormone synthesis), but not the free hormone, are stored in the thyroid. However, the blood contains a large reservoir of protein-bound thyroid hormone. P.572 Major Systems The pituitary gland (OHCM6 p.318) Pituitary structure The pituitary gland is situated beneath the hypothalamus of the brain, in a depression, (the pituitary fossa or sella turcica), of the skull. The human pituitary comprises anterior and posterior lobes. The anterior pituitary consists of distinct endocrine cell types which produce and secrete the various hormones. The posterior pituitary is formed by the axons and terminals of magnocellular neurosecretory neurones originating in the hypothalamus. Pituicytes (a type of glial cell) surround and support the terminals. The posterior pituitary hormones are synthesized in the hypothalamus, packed into granules, transported down the axons, and released, by exocytosis, into the systemic veins. Anterior pituitary Thyroid stimulating hormone (TSH)

Actions: TSH acts in the thyroid. It stimulates T3 and T4 production; increases iodine uptake by the thyroid; and stimulates thyroid growth

Control: TSH release is stimulated by thyrotrophin-releasing hormone (TRH) from the hypothalamus and is inhibited by T3 and T4 negative feedback. Secretion of TRH is stimulated by cold and by stress, via the CNS.

Actions: stimulates production and therefore secretion of cortisol from the cortex of the adrenal gland. ACTH also produces some increase in adrenal sex steroids and stimulates growth of the adrenal cortex. Melanocyte-stimulating hormone (MSH) is also cleaved from POMC and stimulates pigmentation of skin via actions on melanocytes

Control: secretion of ACTH is increased by stress. Secretion is pulsatile with a diurnal rhythm (high at 7.00am, low at midnight). Release of ACTH is stimulated by corticotropin releasing hormone (CRH) from the hypothalamus, inhibited by glucocorticoid negative feedback.

Actions: femaleâLH and FSH control growth and development of follicles; ovulation; synthesis of sex steroids by the ovary; growth and secretion of the sex steroid progesterone by the corpus luteum. MaleâLH controls testosterone production by the Leydig cells; FSH stimulates the Sertoli cells and sperm production

Actions: principal role in preparation for lactation (p.622). PRL stimulates the development and growth of secretory alveoli in the breast and milk production. PRL also inhibits the reproductive system at the level of the gonads and pituitary (causes âlactational amenorrhoeaâ in women after delivery of baby)

Control: secretion of PRL is increased by suckling. PRL release is inhibited by dopamine from the hypothalamus. PRL synthesis is stimulated by circulating estrogen.

Growth hormone (GH)

Actions: stimulates long bone and soft tissue growth, both via stimulating the release of IGFs (insulin-like growth factors) from the liver and by direct actions. It is essential for growth after two years postnatal, but only promotes growth if sufficient nutrition is available. GH also exerts complex actions on metabolism (amino acid, fatty acid, glucose). GH has insulin-like effects to promote amino acid uptake by liver and muscle and, therefore, promotes protein synthesis. However, if GH is chronically increased, it has anti-insulin effects. It is one of the hormones that switches metabolism away from glucose use and toward increased oxidation of fat (e.g. in starvation)

Control: secretion is increased via the hypothalamus by hypoglycaemia, stress, and exercise. Hypothalamic factors that regulate GH release are growth hormone-releasing hormone (GHRH) which stimulates and somatostatin which inhibits GH release. Systemic control is via negative feedback by GH at the hypothalamus.

P.574 Pituitary adenomas (OHCM6 p.320) The pituitary gland is composed almost entirely of cells which make hormones. Thus, a benign tumour of this glandâan adenomaâwill often make the same hormone as its cell of origin, but the production of that hormone will not be under the control of the hypothalamus and will usually be produced in excess. Thus, very small tumours in the pituitary, only a few millimetres in diameter, can have extensive effects on the rest of the body. Pituitary adenomas arise predominantly in the anterior pituitary which constitutes about 80% of the pituitary volume. Before the development of immunohistochemistry, the cells in the pituitary were labelled according to their staining properties with various dyes, but this produced confusing names that were not obviously linked to their function (e.g. chromophobe adenoma). These terms may appear in some literature but it is better to refer to the cells by their products, (e.g. growth hormone). The effects of pituitary adenomas will be specific to the hormones which they produce:

Adenomas of growth hormone (GH) producing cells

Pituitary gigantism if occurring before puberty when the epiphyseal plates are still open and long bones can grow

Acromegaly if after puberty, with disproportionate growth of the bones in the jaw, hands, and feet

Adenomas of adrenocorticotrophic hormone (ACTH) producing cells

Cushing’s syndrome (p.582)

Adenomas of prolactin producing cells

Galactorrhea, amenorrhea, loss of libido, infertility

Adenomas of thyroid stimulating hormone (TSH) producing cells

A rare (1%) cause of hyperthyroidism.

Adenomas of the other hormone producing cells (such as follicle-stimulating hormone and luteinizing hormone producing cells) in the anterior pituitary can occur, but they are much less common than those listed above. Sometimes pituitary adenomas do not produce hormones but they expand within the confined space of the sella turcica and cause pressure atrophy of the remaining pituitary with resultant deficiencies of all the pituitary hormones. This leads to end endocrine organ deficiencies such as hypothyroidism, hypoadrenalism, etc. Since the pituitary gland is confined in the pituitary fossa, with the only space available for expansion being superior to this, then structures above it may be compressed by pituitary adenomas. The optic chiasma lies immediately above the pituitary fossa, so a pituitary adenoma may cause pressure atrophy on this with a resultant defect in the lateral fields of visionâa bitemporal hemianopia. P.575 P.576 The thyroid Lies anterior to the 2ndâ4th rings of the trachea and the lateral lobes extend up on either side of the trachea and larynx. Control of thyroid hormone production and secretion

Epithelial cells of the thyroid (follicular cells) are arranged into follicles around a lumen filled with colloid. The cuboidal follicular cells synthesize thyroglobulin which is released into the colloid

C cells (parafollicular cells), which release the peptide hormone calcitonin (p.593), are located in the base of the follicle epithelium

Production requires iodide. A sodium/iodide symporter on the basal membrane of follicular cells traps and pumps in iodide from the plasma

A thyroperoxidase enzyme on the apical plasmalemma oxidizes the iodide to iodine, iodinates tyrosyl residues in the thyroglobulin, and couples tyrosyl residues to produce the thyroid hormones T4 (thyroxine) and T3 (tri-iodothyronine) still bound in the thyroglobulin and, hence, inactive

Thyroid stimulating hormone stimulates endocytosis of colloid and its digestion by lysosomes, to free T4 and T3

The main thyroid product (T4) is not the metabolically active hormone. Metabolism of T4 to produce active T3 occurs primarily in the liver by type I (5â²)-deiodinase.

Mechanism of action of thyroid hormones

Thyroid hormones are transported into cells and T3 acts on nuclear receptors (TRs) which act on response elements (TREs) in gene promoters

This interaction results in stimulation or inhibition of the production of many different mRNAs and, therefore, proteins. Sensitivity to T3 is regulated via the number of TRs.

Effects of thyroid hormones

Thyroid hormones act on almost every tissue of the body but have little metabolic effect in the brain, spleen, or testis. They act to increase the basal metabolic rate which increases O2 use and heat production

Stimulate production of Na+/K+ ATPase (which uses 20â45% of all ATP)

Stimulate RNA polymerase I and II activity and, thereby, production of many proteins; stimulates protein degradation; when T3 is excessive, degradation > production

P.579 P.580 The adrenal gland The adrenal gland comprises an inner medulla that secretes the catecholamines, noradrenaline and adrenaline, and an outer cortex that secretes steroid hormones. The adrenal glands are located just medial to the upper pole of each kidney. Structure The adrenal medulla is made up of chromaffin cells packed with granules which store large amounts of adrenaline and noradrenaline. The adrenal cortex is made up of sheets of cells surrounded by capillaries and arranged in three zones: the outer zona glomerulosa which makes aldosterone; middle zona fasciculata which makes cortisol; and inner zona reticularis which makes small amounts of androgens. Adrenal medulla

Actions: preparation for emergency physical activity. The adrenal medulla contributes 10% of the total sympathetic nervous system response to stress and so, thus, is not vital. (p.597)

Receptors: Mineralocorticoid (MR) receptors are present in the nuclei of only a few cell typesâkidney collecting tubule epithelia, salivary and sweat glands

Actions: In the kidney, aldosterone regulates ion transport in the kidney collecting tubules in order to stimulate reabsorption of Na+ in exchange for secretion of K+, H+, NH+3. There is a 2hr lag in the response to aldosterone as MR effects are via stimulating transcription of the Na/K ATPase protein. In salivary and sweat glands, aldosterone regulates ion transport to retain sodium

Adrenal androgens (DHEA) DHEA (dehydroepiandrosterone) is produced and released from the adrenal cortex zona reticularis. DHEA is a weak androgen which is a very minor component of adrenal secretions. P.582 Cushing’s syndrome (OHCM6 p.310) Definition Excess glucocorticoid hormones in the body, from whatever source. Mechanisms (Fig. 9.1)

Pituitary adenoma producing excess adrenocorticotrophic hormone (ACTH) because it no longer responds to the normal homeostatic feedback loop. The excess ACTH then stimulates the adrenal cortex to produce excess glucocorticoid hormones. This is also known as Cushing’s disease

Adenoma of the adrenal cortex which has become autonomous from the pituitaryâadrenal feedback loop and produces excess glucocorticoids

Excess ACTH administered by the medical profession or produced endogeneously by a tumour (such as small cell lung cancer)

Excess glucocorticoid steroids, (e.g. prednisolone) administered by the medical profession. This was the most common mechanism for a few decades, since steroids were powerful drugs that could control severe allergic and inflammatory processes such as asthma or rheumatoid arthritis. Fortunately, more specific drugs are now available for some conditions, (e.g. asthma) and in others, âsteroid-sparingâ immuno suppressants, (e.g. azothioprine) are used to reduce the risk or magnitude of Cushing’s syndrome.

Complications of Cushing’s syndrome

Diabetes mellitus

Proximal muscle weakness

Decreased immunity to infections

Osteoporosis

Truncal obesity

Hirsutism

Depression, psychosis.

Fig. 9.1 Mechanisms of Cushing’s syndrome. Arrows indicate either an excess of ACTH or glucocorticoids.

P.583 Hyperaldosteronism (OHCM6 p.314) Definition Excess production of the aldosterone hormone by the adrenal cortex. Causes

Primary

Adrenal cortical adenoma with autonomous production of aldosterone

Primary adrenal cortical hyperplasia

Secondary: normal response to activation of the reninâangiotensin system

Congestive heart failure

Decreased renal perfusion, (e.g. renal artery stenosis), so the juxtaglomerular apparatus senses a lack of perfusion and produces more renin

NB Synergism with other hormones involved in metabolic control: catecholamines, glucocorticoids, growth hormone all stimulate liver conversion of glycogen to glucose. Somatostatin Peptide hormone made in Î´ cells of pancreas. â¢ Actions: Inhibits the secretion of both insulin and glucagons (paracrine action); role in the physiology of the islets is as yet uncertain. P.586 Diabetes mellitus (OHCM6 pp.292â9) Diabetes mellitus is, as yet, an incurable condition that is diagnosed as a chronic increase in blood glucose levelsâhypergylcaemia. The condition is broadly divided into two types, depending on the underlying cause:

Type 1 diabetes (OHCM6 p.292) (formerly âinsulin-dependent diabetes mellitusââIDDM) is caused by an inability to synthesize sufficient insulinâthe hormone responsible for stimulating uptake of glucose into cells. Insulin is usually synthesized in Î²-cells of the Islets of Langerhans in the pancreas, but they are destroyed by an autoimmune response early in the life of susceptible individuals (onset usually occurs before children reach 10 years of age). The trigger for this response is believed to be due to an environmental stimulus in individuals with a genetic predisposition to the condition. Although the child of a parent with type 1 diabetes is at increased risk of developing the disease, the risk is relatively small (<2% if the mother is affected, <6% if the father is affected) unless both parents have the disease, in which case genetic counselling should be sought.

Type 2 diabetes (OHCM6 p.294) (formerly ânon-insulin-dependent diabetesââNIDDM) includes a wide range of disorders that develop over many years, often later in life, ultimately leading to hyperglycaemia. In cases where a specific cause can be identified, reduced secretion of insulin or a reduction in the effectiveness of insulin to facilitate uptake of glucose into cells (so-called insulin resistance) is implicated. However, up to 98% of cases are âidiopathicâ, meaning that no specific cause has been identified.

There is a far clearer genetic link to type 2 than to type 1 diabetes, with people of Asian or Afro-Carribean ethnic origin, and those with a family history of diabetes or gestational diabetes at increased risk of developing the disease. Furthermore, there are a number of rare inherited diseases, including MODY (dominantly inherited type 2 diabetes), mitochondrial diabetes, and insulin-resistant diabetes (due to genetic defects in the insulin receptor [type A] or autoimmune destruction of the receptor [type B]). An increasingly prominent risk factor for diabetes is obesity, probably due to downregulation of insulin receptors in response to increased insulin production (hyperinsulinaemia). The rise in prevalence of obesity in Western countries is thought to be responsible for the emergence of childhood type 2 diabetes. Gestational diabetes is a specific term relating to pregnant women who are diagnosed with hyperglycaemia during routine plasma glucose tests at ~28 week gestation. Blood glucose levels typically return to normal within 6 weeks of birth, but the condition may be indicative of a predisposition to type 2 diabetes later in life for both mother and child. Babies of mothers with gestational diabetes are often born overweight because of the growth-stimulating effects of increased foetal insulin secretion in response to high glucose levels derived from the mother. P.587 Complications of diabetes (OHCM6 p.296) The major complications associated with persistent hyperglycaemia relate to the cardiovascular system. Broadly, the effect of diabetes on the cardiovascular system can be divided into microvascular complications in the eyes, kidneys, and nerves, and complications pertaining to the major arteries, including coronary artery disease, stroke, and peripheral vascular disease. The principle cause of most, if not all, of these complications is diabetes-induced hypertension, although glycation of haemoglobin is also crucial in microvascular disease. The precise mechanism by which persistent hyperglycaemia induces hypertension has yet to be fully elucidated, but increased generation of reactive oxygen species and the associated dysfunction of protective endothelial effects are believed to be important. Diagnosis (OHCM6 p.292, 294) Diabetes is notoriously difficult to diagnose: patients generally present having suffered weight loss, but other symptoms include tiredness, dry mouth, ketoacidosis (overaccumulation of ketones in the blood and urine as a by-product of the metabolism of lipids that are used as a substitute fuel for energy instead of glucose which is poorly absorbed by cells in the absence of insulin), and, in more advanced cases, foot or leg ulcers and sepsis. Routine screening of patients’ plasma and urine has improved diagnosis. Patients with suspected diabetes are subjected to an oral glucose tolerance test in which they fast for 12hr, after which a baseline blood sample is taken. Patients are then given an oral load of 75g of glucose; a second sample is taken 2hr after the oral glucose load. Generally accepted limits for diagnosis of diabetic patients are given in Table 9.1 and patients whose glucose levels are elevated but do not exceed the threshold for full-blown diabetes are said to have impaired glucose tolerance.

1. A âcasualâ plasma sample (i.e. taken without regard for time of last meal) of â¥11.1 mmol/l can also be indicative of diabetes but usually needs to be confirmed by a glucose tolerance test or by repeating on another day.2. In the absence of symptoms, a positive glucose tolerance test might have to be supported by elevated glucose levels at a second timepoint (e.g. â¥11.1 mmol/l at 1 hr).

P.588 Treatment (OHCM6 p.295, 297) Impaired glucose tolerance and mild gestational diabetes are often treated through changes in diet and lifestyle, in an effort to avoid exacerbating the problem through high carbohydrate intake and weight gain. A similar approach is often used in patients where obesity is a primary cause of diabetes but is supplemented with drugs that stimulate insulin secretion, such as sulphanylureas and meglitidine analogues. Ultimately, however, these patients and their non-obese counterparts, as well as patients with type 1 diabetes are commonly prescribed insulin to alleviate the symptoms. The peptide nature of insulin prevents the use of an oral preparation, requiring patients to inject subcutaneously immediately prior to meals. The inherent danger of this form of treatment is that, should a patient fail to eat after injecting, blood glucose can fall fatally low (hypoglycaemia). Ultimately, diabetes is an incurable condition; treatments aim to improve the lifestyle of patients and to reduce the risk of serious diabetes-related conditions. P.589 P.590 Gastrointestinal hormones

Functions: GI hormones, with the enteric and autonomic nervous systems, integrate and co-ordinate the mechanisms which move, digest, and absorb the various meals that are ingested. They control GI tract exocrine and endocrine secretion, motility, growth, and blood flow

Routes: hormones released from gut endocrine cells act via endocrine, paracrine, neurocrine routes, and possibly also via the gut lumen. Peptides are also released from nerves of the enteric nervous system

Gut endocrine cells are part of the GI tract epithelium, variably positioned in crypts or villi; hormone is secreted basally; most have sensory microvilli on an apex open to the gut lumen. Most gut hormones are peptides produced from larger precursors, so different molecular forms of the hormones are found.

Gastrin

Distribution: G cells of gastric antrum crypts; some duodenal cells

Synthesis: produced as prohormone preprogastrin, cleaved to progastrin and, in turn, to gastrin

Rapid effects: stimulates Ca2+ flux from bone across osteoblasts which lay down new bone and line the bone surface; PTH reorganizes osteoblasts so that they become separated to allow: calciumef flux from matrix; and access of osteoclasts (which break down bone). In the long term, osteoclasts are activated via osteoblasts (protein synthesis needed) which break down bone; excess PTH limits growth of osteoblasts and bone matrix synthesis, causes destruction of bone

Reninâangiotensin system Renin is an acid protease produced by juxtaglomerular cells in the afferent arterioles of glomeruli, in response to sodium depletion, hypotension, dehydration, poor renal artery blood flow, sympathetic stimulation. This cleaves plasma angiotensinogen to angiotensin I, which is then cleaved by angiotensin-converting enzyme (in the lungs) to the active angiotensin II, which stimulates aldosterone secretion, thirst, and vasoconstriction. P.595 P.596 Stress The stress response Stress Any change/event that either disrupts, or threatens to disrupt, homeostasis to an unusual degree. Stressor Any severe disturbance.

The stress response is, at least in the short term, counter-homeostatic. It raises blood pressure, blood sugar, ventilation, etc.

The purpose of these changes is to prepare the body to meet an emergency situation. It has evolved in order to allow the individual to survive the emergency, and return to normal homeostasis when the stress is no longer present

It involves a short-term alarm reaction; and a more long-lasting resistance reaction

The hypothalamus controls and co-ordinates the stress response via its actions on the autonomic nervous system and the endocrine systems. It receives inputs from:

Decreased insulin causes reduced use of glucose by muscle and fat, conserving glucose for the brain (muscle runs on glycogen, free fatty acids)

Pupil dilation, eyelid retraction, accommodation for distant vision

Increased activity of preganglionic sympathetic nerves stimulates the adrenal medulla to release adrenaline which supplements and prolongs all the above reactions; it also causes increased liver glycogenolysisâmobilizes glucose to avoid risk of brain hypoglycaemia

Stimulates hormone-sensitive lipaseâmobilizes free fatty acids for use as energy substrates by many organs.

P.598 The resistance response If the stress is more long-lasting, more prolonged effects of the acute response and more chronic responses occur to produce the resistance reaction. These involve the slower results of the sympathetic nerve stimulation and actions of various hormones that are more prolonged than those of the catecholamines. Sympathetic nerves stimulate juxtaglomerular cells of the kidney. This results in the production of angiotensin II which both causes vascular constriction and also stimulates mineralocorticoid (aldosterone) release which:

Increases Na+ reabsorption which causes water retention, maintains a high BP, and counteracts fluid loss

Increases elimination (exchange) of H+ ions (accumulate as a result of the increased catabolism).

Inhibits leukocyte translocation from blood to sites of tissue damage or infection

Stimulates lymphocyte destruction

Glucocorticoid selective drugs are used therapeutically to treat inflammatory diseases such as asthma and eczema (e.g. prednisone, betamethasone) but have some mineralocorticoid effects

Reproduction and lactation: inhibits, in part by inhibition of LH and PRL, release from the anterior pituitary gland (pregnancy is a non-essential metabolic drain on resources).

P.599 Hypothalamic TRH Stimulates the release of TSH and, therefore, thyroid hormones. Thyroid hormones increase the metabolic rate and the catabolism of glucose, fats, and proteins (p.576). Note In starvation (which is a particular form of stress), glucocorticoids reduce the conversion of T4 to T3 in the liver, blunting the catabolic response. Hypothalamic GHRH GHRH stimulates the release of GH which, when secreted in a prolonged manner (normally it is secreted in short pulses every 4â6hr), causes:

Increased liver breakdown of fats to fatty acids and glycerol

Increased liver conversion of glycogen to glucose.

By these means, the resistance reaction allows the body to continue fighting a stressor long after the effects of the acute alarm reaction. It produces the energy and circulatory changes required for the performance of strenuous tasks, fighting infection, avoiding fatal haemorrhage. If there is greatly increased metabolism, blood glucose returns nearly to normal during the resistance reaction as input = output; blood pH is controlled by the kidney. However, blood pressure remains raised because of retention of water. When the stress is prolonged

Within the hypothalamus, CRF, glucocorticoids, opioid peptides reduce GnRH secretionâavoid risk of pregnancy and a further drain on metabolic resources

In the hippocampus, glucocorticoids act on glucocorticoid receptors to modify emotional reactionsâinduce mild euphoria, diminishing the psychic effects of the stress.

Chronic stress at different ages

In utero: the stress of undernourishment leading to low birth weight is associated with a significant increase in hypertension, diabetes mellitus, and lower life expectancy

Childhood: chronic stress in childhood is associated with retarded growth

Aged: the morning peak of cortisol occurs earlier in the aged; the cortisol response to the stress of an operation is also prolonged.

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